The training of domestic animals and especially young dogs, to achieve "housebroken" status is a universal problem. One of the particular problems associated with such training is to prevent nighttime micturition or urination. There is a clear need in the art for methods and compositions which would assist in training of the young domestic animals to minimize or totally avoid nighttime urination.
It is known in the art that anticholinerics or antimuscarinics such as atropine possess side effects including retention of urine. See U.S. Pat. No. 3,436,458 and U.S. Pat. No. 4,644,003. Further, various studies have been reported concerning testing of atropine and related compounds in various medical areas.
Chemical Abstracts, volume 89, page 157365, is an abstract on a Russian article regarding the effect of atropine and other compounds on the kidney excretion of hemocoagulating and fibrinolytic compounds in urine. In this abstract, atropine was found to stimulate urinary elimination of thromboplastic and antiheparin substances but depressed excretion of antithrombins in cats.
Chemical Abstracts, volume 81, page 86125b, is an abstract of a Netherlands article on the effect of administration of certain cholinergic drugs including atropine sulfate on water diuresis and electrolyte excretion in goats. In this study, atropine was found to prevent antidiuretic effects and increased electrolyte secretions when used as a pretreatment material.
Chemical Abstracts, volume 79, page 73604r, is an abstract of a Polish article regarding the effect of certain compounds on the secretory action of histamine-stimulated gastric mucosa in dogs. In this article, histamine caused secretion in dogs but atropine was found to inhibit this secretion.
Chemical Abstracts, volume 73, page 42210f, is directed to the inhibition of plasma antidiuretic activity subsequent to bleeding in sheep treated with atropine and other agents. In this abstract, atropine was one of several compounds studied with respect to antidiuretic activity in water loaded sheep. The study was based on the drugs ability to inhibit the increase in antidiuretic hormone.
In addition to these publications, the following publications from Chemical Abstracts describe work done in connection with atropine on humans such as the human bladder muscle. These abstracts are as follows:
Chemical Abstracts, Volume 103, page 206244M, 1986
Chemical Abstracts, Volume 98, page 138013M, 1983 PA1 Chemical Abstracts, Volume 66, page 62398G, 1967 PA1 U.S. Pat. No. 2,594,296 PA1 U.S. Pat. No. 3,063,901 PA1 U.S. Pat. No. 3,062,720 PA1 U.S. Pat. No. 3,923,990.
In all of these abstracts, atropine is found to have an inhibitory effect on the human bladder.
The following patents disclose other uses of atropine and mixtures thereof:
It is also known to administer atropine to domestic animals and particularly young dogs for various reasons. Thus, in a publication by Boyd et al, Canada M.A.J., Volume 32, page 821-824, 1960, there is described a study of chronic atropinization and fibrocystic disease of the pancreas in attempts to produce in young puppies a condition similar to fibrocystic disease of the pancreas in children. The work was performed upon puppies wherein atropine was injected subcutaneously dissolved in olive oil. In this study various measurements were made including testing of the urine in the urinary bladder. The results of the study indicated that the lethal dose of atropine was in the range of 125.+-.mg/kg in puppies and 108.+-.10 mg/kg in kittens. The corresponding value for atropine sulfate was 181.+-.12 mg/kg in puppies. In addition, high dosage amounts caused various other medical problems. It is pointed out in Boyd et al that chronic administration of atropine produced in puppies a syndrome characterized by protracted cholinergic inhibition, stimulation followed by depression of the central nervous system, loss of weight and increasing cachexia. Impairment of several organs such as the gastrointestinal tract, pancreatic acinar glands, livers and thymus glands was also noted. The lungs showed pneumonia-like congestion and the output of respiratory tract fluid was increased. There was also a disturbance of salt and water metabolism.
In a further study by Boyd et al, Canadian M.A.J., volume 85, page 1241-1244, 1961, the acute toxicity of atropine sulfate was studied in rabbits. Various problems were encountered on administration of these relatively high dosages of atropine sulfate.
In a publication by Albanus, Acta Pharmacol, et toxicol, vol. 26, page 571-582, 1968, the fate of atropine in the dog was studied. The purpose of this study was to determine the metabolic fate of atropine in dogs. In the study atropine was administered by injection to dogs weighing between 10 and 15 kg with the injection being at the rate of 0.5 mg per kg expressed as atropine sulfate.
A similar study by Winbladh, Acta Pharmacol et toxicol, vol. 31, pages 46-64, 1973, discusses the fate of atropine in the puppy. In this study, atropine is administered by subcutaneous injection into new born, 3 and 6 week old, 3 month old and adult dogs in tritium labeled form. The purpose of this study was to determine the effect on various organs and determine the areas of the body which would bind to the atropine.
In this invention it has been discovered that antimuscarinics or anticholinerics such as atropine can be utilized in carefully controlled harmless dosage amounts to assist in training to housebroken status of young domestic animals.